Process for the preparation of stable dispersions of at least one water-immiscible liquid phase in an aqueous phase

ABSTRACT

A process for the preparation of a stable emulsion of at least one water-immiscible liquid phase L in an aqueous phase D is described which comprises mixing the liquid phase or phases L with a dispersion of spheres in an aqueous phase D, the spheres having an average diameter of 0.025 to 5 microns and consisting of substantially concentric lipid laminae encapsulating an aqueous phase E between them, the lipid or lipids constituting the laminae being ionic or nonionic amphiphilic substances capable of forming a lamellar phase in water, and subjecting the whole to mechanical agitation so as to disperse the phase (or phases) L in the phase D in the form of droplets having an average diameter of 0.1 micron to a few microns.

This application is a continuation-in-part of our application Ser. No.900,772 filed Aug. 26, 1986 which, in turn, is a continuation of ourSer. No. 279,518, filed July 1, 1981, now abandoned.

The present invention relates to a process for the preparation of stabledispersions of at least one water-immiscible liquid phase in an aqueousphase.

It is known that if a water-immiscible liquid phase is mixed into anaqueous phase by mechanical agitation, for example by means of anultra-disperser, the stability of the dispersion most frequentlyrequires the addition of an emulsifying agent, the molecules of whichare adsorbed onto the surface of the droplets of the water-immiscibleliquid phase to form a kind of continuous membrane which prevents directcontact between two adjacent droplets, for example during shock. Thedroplets of water-immiscible liquid phase can contain substances solublein an organic medium. However, it can be desirable to producedispersions which contain, in micro-reservoirs similar to those formedby the abovementioned droplets, water-soluble substances capable ofacting in coordination with that of the liposoluble substances containedin the droplets.

It is furthermore known to produce aqueous dispersions of small lipidspheres (see French Patent 2,221,122 and U.S. Pat. No. 4,217,344). Thesesmall lipid spheres consist of several substantially concentric lipidlaminae separated from one another by layers of aqueous phase; thesesmall spheres can be used to encapsulate water-soluble active substancesin the aqueous compartments between the lipid layers.

According to the present invention, it has been found that it ispossible to stabilize droplets of water-immiscible liquid by thepresence, in the same dispersion, of such small lipid spheres. Thisobservation will be particularly surprising to those skilled in the artbecause, although it is possible to imagine that the amphiphilic lipidsconstituting the small spheres could act as an emulsifier by beingadsorbed onto the surface of the oil droplets, one would neverthelessexpect that such stabilization of the oil droplets would cause thedestruction of the concentric laminae of the small spheres. On thecontrary, it has been found that these small spheres stabilize thedroplets of immiscible liquid in the overall dispersion, and that,conversely, the droplets of water-immiscible liquid contribute to thestability of the small lipid spheres. The dispersions thus obtainedpossess a remarkable stability under normal storage conditions; thesmall spheres retain their integrity, which is all the more surprisingbecause the organic liquids generally have a solvent action towards theamphiphilic lipids of the small spheres.

The dispersions obtained by the process according to the invention thusconsist of a continuous aqueous phase in which droplets of immiscibleliquid, on the one hand, and small spheres of concentric lipid laminae,on the other hand, are held in suspension; it is believed that thedroplets are held in suspension by the small spheres adsorbed on theirsurface. The formation and the stability of such dispersions of coursedepend firstly on the nature of the immiscible liquid to be dispersed,secondly on the nature of the amphiphilic substances forming the wallsof the small spheres, and lastly on the conditions under which theprocess is carried out.

The present invention provides a process for the preparation of a stabledispersion consisting of droplets of at least one water-immiscibleliquid phase L dispersed in a continuous aqueous phase D. The sphereshave an average diameter of 0.025 to 5 microns and consist ofsubstantially concentric lipid laminae encapsulating an aqueous phase Ebetween them. The lipids constituting the laminae are ionic or nonionicamphiphilic substances which are capable of forming a lamellar phase inwater. This dispersion and the liquid phase (or phases) L are mixed, andthe whole is subjected to mechanical agitation in order to disperse thephase (or phases) L in the phase D in the form of said droplets havingan average diameter of 0.1 micron to a few microns. The aqueous phase Dcontains no amphiphilic substance other than the amphiphilic substanceconstituting the laminae of the said spheres.

In a preferred embodiment, in order to mix the dispersion of smallspheres with the liquid phase (or phases) L, the said liquid phase (orphases) L are added to the dispersion of small spheres; eachwater-immiscible liquid phase L should consist of one or more compoundshaving a molecular volume of at least 200 cm³ /mol; preferably, a singleliquid phase L is dispersed in the phase D.

Any known process can be used to produce the dispersion of the smalllipid spheres in the aqueous phase D. For example, it is possible todissolve the lipids in a volatile solvent, form a thin film of lipids onthe walls of a flask by evaporating off the solvent, introduce theaqueous phase E to be encapsulated into the said flask, and agitate themixture mechanically until the dispersion of small spheres of thedesired size is obtained; in this case, the aqueous phases D and E arenecessarily identical. It is preferred to use the process described inU.S. Pat. No. 4,217,344 the disclosure of which is hereby incorporatedby reference. This process consists in forming a plane lamellar phase byintroducing the aqueous phase E to be encapsulated into the liquidlipids, at a temperature slightly above the melting point of the lipids,subsequently adding, to the lamellar phase obtained, an aqueousdispersion phase D, which may or may not be identical to the aqueousphase E, and in vigorously agitating, for example mechanically, in orderto convert the plane lamellar phase into a dispersion, in the aqueousphase D, of small lipid spheres encapsulating the aqueous phase E.Depending on the means used to produce the dispersion e.g.ultra-disperser and/or ultrasound, and depending on the agitation time,e.g. from 15 minutes to a few hours, small spheres having an averagediameter from 0.025 to 5 microns are generally obtained.

The dispersion of the water-immiscible liquid phase (or phases) L isadvantageously produced with the aid of an ultra-disperser, at atemperature in the region of ambient temperature, which represents asignificant advantage from the economic point of view, for the stabilityof the constituents of the composition, in particular if they arevolatile or oxidizable, and for safety. The average diameter of thedroplets of liquid L obtained is from 0.1 to a few microns.

The lipids used for the preparation of the small spheres are ionic ornonionic amphiphilic substances of natural or synthetic origin, whichcontain, per molecule, one or more long hydrocarbon chains or one ormore hydrophilic groups, in general hydroxyl, ether, carboxyl,phosphate, amine or ammonium groups.

Amongst the ionic amphiphilic substances, it is preferred to use naturalphospholipids, for example egg lecithin, soya lecithin or sphingomyelin,synthetic phospholipids, for example dipalmitoyl-phosphatidyl-choline orhydrogenated lecithin, and cationic or quaternary compounds, for exampledialkyldimethylammonium chloride or bromide such as didodecyl- ordistearyldimethylammonium chloride or bromide; it is also possible touse amphoteric compounds or anionic compounds.

Amongst the nonionic amphiphilic compounds, it is preferred to use:

1) the straight or branched polyglycerol ethers of the formulae,respectively ##STR1## and

n representing an average statistical value from 1 to 6 (in a mixture)and R being a saturated or unsaturated, straight or branched aliphaticchain having 12 to 30 carbon atoms, a hydrocarbon radical of a lanolinalcohol or a 2-hydroxyalkyl radical of a long-chain α-diol;

2) polyoxyethylenated fatty alcohols and polyoxyethylenated sterols;

3) oxyethylenated or nonoxyethylenated polyol esters;

4) glycolipids of natural or synthetic origin, for example cerebrosides;and

5) ethers or esters of polyols containing two long-chain alkyl groups(having at least 8 carbon atoms) as the hydrophobic residue.

Various additives can be associated with the lipid compounds which areto form the small spheres; in order to modify the permeability or thesurface charge of the said small spheres. In this respect, there may bementioned the optional addition of long chain alcohols and diols,sterols, for example cholesterol, long chain amines and their quaternaryammonium derivatives, dihydroxyalkylamines, polyoxyethylenated fattyamines, long-chain aminoalcohol esters and salts and quaternary ammoniumderivatives thereof, phosphoric acid esters of alcohols and inparticular phosphoric acid esters of fatty alcohols, for example dicetylphosphate, alkyl-sulphates, for example sodium cetyl-sulphate, andcertain polymers such as polypeptides and proteins.

From 2 to 10% of lipids, relative to the total weight of the dispersionof small spheres to be mixed with the liquid phase L, are generally usedto form the dispersion of small lipid spheres. In a preferredembodiment, the aqueous phases D and E are isoosmotic, and in thesimplest embodiment, the aqueous phases D and E are identical.

At least one compound which is a hydrocarbon, halocarbon, polysiloxane,an ester of an organic or mineral acid, or an ether or polyether isadvantageously chosen in order to form a liquid phase L. Hexadecane andparaffin oil may be mentioned amongst the hydrocarbons. Representativehalocarbons include, for instance, perfluorodecahydronaphthalene andperfluorotributylamine.

According to an advantageous embodiment, the liquid phase L isintroduced into the dispersion of small spheres in an amount from 2 to70% by weight, relative to the weight of the dispersion of smallspheres. It is preferred to introduce the liquid phase L into thedispersion of small spheres in an amount from, say, 20 to 2,000%,relative to the weight of amphiphilic substance(s) contained in thedispersion of small spheres.

The present invention also provides the stable dispersions obtained bythe process of this invention. The field of application of thesedispersions is very broad because it combines the field of emulsions ofdifferent types with dispersions of small spheres of ionic or nonioniclipids. The small lipid spheres can be used to encapsulate, betweentheir concentric lipid laminae, layers of aqueous phase containingwater-soluble active substances; furthermore, the lipid layers of thesmall spheres can contain active organic substances. Amongst thewater-soluble active substances, there may be mentioned organic orinorganic compounds having a biological, microbiocidal, fungicidal,insecticidal, vitamin or photosensitive activity, medicaments, chemicalreagents, catalysts, dyestuffs, complexing agents and gases (O₂ or CO₂).Amongst the liposoluble active substances, there may be mentionedantibiotics and antioxidants.

In the dispersions according to the invention, the presence of thedroplets of liquid phase L constitutes an additional advantage becausethe droplets can contain substances soluble in an organic medium, theactivity of which can be identical to or different from that of thesubstances trapped in the small spheres, the difference between the twogroups of substances resulting essentially from opposite solubilities.By virtue of its function as solvent or vehicle, the liquid phase Litself can make it possible to bring an active substance to anapplication site; by way of example, perfluorinated compounds aretransporters of oxygen and carbon dioxide, which makes it possible toenvisage their use as blood substitutes. In certain cases, the liquidphase L can act as a lubricant, spreading agent, cleaning agent orpolishing agent. If its molecular weight is relatively low, thevolatility of the liquid phase L is such that it disappears afterdeposition; this can be very advantageous in surface-treatment processesor surface-coating processes. The liquid phase L can also contain apolymer, an oligomer, a prepolymer or a monomer; it can also containfillers or additives such as dyestuffs, opacifiers or gelling agents.

The continuous aqueous phase of the dispersion according to theinvention can itself contain dissolved substances similar to ordifferent from the substances contained in the aqueous or lipid layersof the small spheres and in the liquid phase L.

It is to be understood that the small spheres behave as a first type ofmicro-reservoir, which slowly releases the trapped water-soluble andliposoluble substances. Furthermore, the droplets of liquid phase Lconstitute a second type of micro-reservoir, in which the dissolvedcompounds can be exchanged with an organic substrate, which may be thatof a living being. The actions of the small spheres and liquid phase Lcan combine, complement one another or give rise to synergism. Forexample, the release of the active substances contained in the smallspheres can be accelerated by the combined action of the temperature andthe solvent power of the liquid phase L; this can be useful for carryingout a monomer polymerization operation or a crosslinking operation.

The following Examples further illustrate the present invention.

EXAMPLE 1 First step: Preparation of the dispersion of small spheres4.275 g of a product of the general formula: ##STR2## in which formula Ris a hexadecyl radical and n has an average statistical value of 3,4.275 g of cholesterol and 0.45 g of dicetyl phosphate are weighed intoa stainless steel pot.

This mixture is heated to a temperature of about 110° C. until a clearliquid lipid phase is obtained, and this is then cooled to a temperatureof 90° C. 22.5 g of a 0.5M aqueous solution of glucose are added. Themixture is stirred gently with a spatula until an apparently homogeneousphase is obtained.

This is cooled to a temperature of 70° C. and 68.5 g of the same 0.5Maqueous solution of glucose are added. The whole is agitated for 10minutes by means of an ILA ultra-disperser, model CX 1020, rotating at25,000 rpm. It is then cooled to 40° C.

Second step: Introduction of the water-immiscible liquid phase L

12.5 g of perfluorodecahydronaphthalene are added to 100 g of thedispersion of small spheres obtained in the first stage. This mixture isagitated for 5 minutes by means of the same ultra-disperser as that usedat the end of the first stage of the present example.

This gives a stable dispersion in which the small spheres have anaverage size of less than 1 micron and in which the droplets have anaverage size of less than 1 micron. This dispersion can be used as ablood substitute.

In order to study the characteristics of this dispersion, the amount ofglucose encapsulated by the small spheres, which are used as aperfluorodecahydronaphthalene stabilizer, is determined. For thispurpose, the swelling S of the lipids constituting the small spheres isdetermined. If the weight of aqueous solution of glucose encapsulated isdesignated by WS and the weight of lipids is designated by WL, theswelling S is calculated by the formula: ##EQU1##

To carry out this determination, given that the weight of lipids WL usedis known, it is necessary to determine the weight WS. 5 g of the finalproduct are placed in a collodion dialysis bag, and this is dialyzedagainst 200 g of a 1.5% strength aqueous solution of sodium chloride(isoosmotic), whilst stirring. The amount of glucose not encapsulated bythe vesicles is determined in the external saline medium after thedialysis equilibrium time (24 hours). The amount of glucoseencapsulated, WS, is deduced therefrom and it is calculated that S=86%.

By way of comparison, the swelling of the small spheres before they areused as an oil stabilizer is determined by dialyzing 5 g of thedispersion obtained at the end of the first stage of this exampleagainst 200 g of an isoosmotic solution of sodium chloride. The SwellingS is found to be 87%.

EXAMPLE 2 First step: Preparation of the dispersion of small spheres

In a glass flask, 6.75 g of soya lecithin marketed under the name"Epikuron 200" by "Lukas Meyer", 1.8 g of cholesterol and 0.45 g ofdicetyl phosphate are dissolved in 20 ml of chloroform.

This solution is lyophilized with the aid of a Virtis apparatus, model1020. 91 g of a 1M aqueous solution of glucose are added to theanhydrous lipid mixture obtained after lyophilization. This mixture isleft to swell for 2 hours at a temperature of 40° C., under a nitrogenatmosphere. It is agitated for 10 minutes by means of theultra-disperser defined in Example 1, and then cooled to ambienttemperature. This gives a dispersion of small spheres.

Second step: Introduction of the water-immiscible liquid phase L

12.5 g of perfluorodecahydronaphthalene are added to 100 g of thedispersion of small spheres obtained in the first stage. This mixture isagitated for 5 minutes, at ambient temperature, by means of theultra-disperser used in the first stage. This gives a liquid dispersionwhich contains small spheres having a diameter of less than 1 micron andperfluorodecahydronaphthalene droplets having an average diameter ofless than 1 micron. This dispersion can be used as a blood substitute.

The swelling of the small spheres used to stabilize theperfluorodecahydronaphthalene was determined. The swelling S was foundto be 74%. The proportion of encapsulated glucose which escapes over 5days is 36%. However, it was not possible directly to determine theswelling of the small spheres before dispersing the oil; in fact, it wasfound that, when dialyzed against 200 g of a 3% strength aqueoussolution of sodium chloride (isoosmotic), the 5 g sample of thedispersion obtained at the end of the first stage deteriorated veryrapidly; the small spheres lose their integrity and re-form a viscousphase which clogs the dialysis bag. It is thus apparent that, in thisexample, the perfluorodecahydronaphthalene droplets stabilize the smallspheres obtained in the first stage. The swelling of the small spheresbefore dispersing the oil was determined by another method, at lowerconcentrations of lipids and glucose and after filtration on a column ofgel; the swelling S is found to be 74%. The proportion of encapsulatedglucose which escapes over 5 days is 45%. It is thus seen that thestability of the encapsulation is improved by the presence of thedroplets of the water-immiscible liquid L.

The process used for the two-step preparation of the dispersionsaccording to the invention, in the examples which now follow, isidentical to that which has been described above in Examples 1 and 2, sothat the examples which now follow only mention the products used andthe corresponding amounts for each of the two steps of each example. Theexamples also mention, if appropriate, the swelling of the small spheresbefore and after dispersing the oil.

EXAMPLE 3 First step: Preparation of the dispersion of small spheres

The following products are used:

Product of the general formula: ##STR3## in which formula R is ahexadecyl radical and n has an average statistical value of 3;

    ______________________________________                                        Sitosterol       4.275       g                                                Dicetyl phosphate                                                                              0.45        g                                                Glucose          8.19        g                                                Water            82.81       g                                                ______________________________________                                    

This gives a dispersion of small spheres.

Second step: Introduction of the water-immiscible liquid phase L

12.5 g of a silicone oil marketed under the name "DOW 344" by "DOWCORNING" are added to the dispersion of small spheres obtained in thefirst step.

The swelling index of the small spheres before dispersing the siliconeoil is 87%; the swelling of the small spheres after dispersing thesilicone oil is 85%. The average diameter of the small spheres in thedispersion obtained is 1 micron; the average diameter of the droplets ofsilicone oil in the dispersion obtained is 2 microns.

The dispersion obtained can be used as an anti-foam agent.

EXAMPLE 4 First step: Preparation of the dispersion of small spheres

The following products are used:

Product of the general formula: ##STR4## in which formula R is ahexadecyl radical and n has an average statistical value of 3;

    ______________________________________                                        Cholesterol      3.8         g                                                Dicetyl phosphate                                                                              0.4         g                                                Cholesterol oleate                                                                             0.8         g                                                Water            91.2        g                                                ______________________________________                                    

This gives a dispersion of small spheres.

Second step: Introduction of the water-immiscible liquid phase L

40 g of perfluorodecahydronaphthalene are added to 100 g of thedispersion of small spheres obtained in the first step. This gives adispersion in which the small spheres have an average diameter of lessthan 1 micron and the perfluorodecahydronaphthalene droplets have anaverage diameter of less than 1 micron.

The dispersion thus obtained can be used as a blood substitute.

EXAMPLE 5

First step: Preparation of the dispersion of small spheres

The following products are used:

    ______________________________________                                        Soya lecithin marketed under the name                                                                  9 g                                                  "Epikuron 145" by "Lukas Meyer"                                               Distilled water         91 g                                                  ______________________________________                                    

This gives a dispersion of small spheres.

Second step: Introduction of the water-immiscible liquid phase L

12.5 g of a hexadecane are added to 100 g of the dispersion of smallspheres obtained in the first step. This gives a dispersion in which thesmall spheres have an average diameter of 0.5 micron and the hexadecanedroplets have an average diameter of 2 microns. This dispersion can beused as a lubricant for textiles.

EXAMPLE 6 First step: Preparation of the dispersion of small spheres

The following products are used:

    ______________________________________                                        Synthetic dipalmitoyl-lecithin                                                                    8.5        g                                              Cholesterol         1.0        g                                              Dicetyl phosphate   0.5        g                                              Glucose             0.1        g                                              NaCl                0.054      g                                              KCl                 0.032      g                                              MgCl.sub.2          0.007      g                                              CaCl.sub.2          0.010      g                                              NaH.sub.2 PO.sub.4  0.0096     g                                              Na.sub.2 CO.sub.3 q.s.                                                                            pH 7.44                                                   Distilled water q.s.                                                                              110        g                                              ______________________________________                                    

This gives a dispersion of small spheres.

Second step: Introduction of the water-immiscible liquid phase L

30 g of perfluorotributylamine are added to 100 g of the dispersion ofsmall spheres obtained in the first step.

This gives a dispersion according to the invention, in which the smallspheres have an average diameter of less than 1 micron and theperfluorotributylamine droplets have an average diameter of less than 1micron. A dispersion of this type can be used as a blood substitute.

EXAMPLE 7 First step: Preparation of the dispersion of small spheres

The following products are used:

    ______________________________________                                        Sodium salt of N-(tallow fatty alkyl)-N-                                                             4.95      g                                            (dodecyl)-N-(N',N'-diethylaminoethyl)-                                        asparagine (described in French                                               Patent 1,397,231)                                                             Cholesterol            3.6       g                                            Dicetyl phosphate      0.45      g                                            Glucose                8.19      g                                            Water                  82.81     g                                            ______________________________________                                    

This gives a dispersion of small spheres.

Second step: Introduction of the water-immiscible liquid phase L

11 g of perfluorotributylamine are added to 100 g of the dispersion ofsmall spheres obtained in the first step. The swelling of the smallspheres before and after the second step is measured at 78%.

This gives a dispersion according to the invention, in which the smallspheres have an average diameter of less than 1 micron and theperfluorotributylamine droplets have a diameter of less than 1 micron. Adispersion of this type can be used as a blood substitute.

EXAMPLE 8 First step: Preparation of the dispersion of small spheres

The following products are used:

    ______________________________________                                        Dioctadecyl-dimethylammonium chloride                                                                  3 g                                                  Distilled water         97 g                                                  ______________________________________                                    

This gives a dispersion of small spheres.

Second step: Introduction of the water-immiscible phase L

12.5 g of hexadecane are added to 100 g of the dispersion obtained inthe first step. This gives a dispersion according to the invention, inwhich the small spheres have an average diameter of 1 micron and thehexadecane droplets have an average diameter of 2 microns.

This dispersion can be used as a lubricant for textiles.

EXAMPLE 9 First step: Preparation of the Dispersion of Small Spheres

The following products are used:

    ______________________________________                                        Oxyethylenated phytosterols with a                                                                       6.75 g                                             statistical distribution having                                               an average value of 5 ethylene oxide                                          units (product marketed under the                                             name "GENEROL 115 E5" by "HENKEL")                                            Cholesterol                2.25 g                                             Distilled water            91.0 g                                             ______________________________________                                    

This gives a dispersion of small spheres.

Second step: Introduction of the Water-Immiscible Liquid phase L

25 g of paraffin oil are added to 100 g of the dispersion obtained inthe first step. This gives a dispersion according to the invention, inwhich the small spheres have an average diameter of 0.5 micron and theparaffin oil droplets have an average diameter of 1 micron.

This dispersion can be used as an intestinal lubricant.

What is claimed is:
 1. A process for the preparation of a stabledispersion comprising droplets of at least one water-immiscible liquidphase dispersed in a continuous aqueous phase, said aqueous phase havingspheres dispersed therein whereby said droplets are stabilized in saiddispersion by the presence therein of said spheres, said processcomprisingmixing by mechanical agitation said water-immiscible liquidphase with a dispersion of spheres in said continuous aqueous phase,said water-immiscible liquid phase consisting of a hydrocarbon, ahalocarbon or polysiloxane, said spheres having an average diameter of0.025 to 5 microns and consisting substantially of concentric lipidlaminae encapsulating an aqueous phase between them, said lipidconstituting said laminae consisting of an ionic or nonionic amphiphilicsubstance capable of forming a lamellar phase in water and saidcontinuous aqueous phase contains, as the only amphiphilic substance,the said ionic or nonionic amphiphilic substance constituting thelaminae of said spheres, all said ionic or nonionic amphiphilicsubstances being enclosed in the laminae of said spheres.
 2. The processof claim 1 wherein said ionic amphiphilic substance is a naturalphospholipid, a synthetic phospholipid, a cationic compound, aquaternary compound, an amphoteric compound or an anionic compound. 3.The process of claim 2 wherein said natural phospholipid is egglecithin, soy lecithin or sphingomyelin.
 4. The process of claim 2wherein said synthetic phospholipid is dipalmitoyl-phosphatidyl-cholineor hydrogenated lecithin.
 5. The process of claim 2 wherein saidquaternary compound is didodecyl dimethyl ammonium chloride, didodecyldimethylammonium bromide, distearyl dimethylammonium chloride ordistearyl dimethylammonium bromide.
 6. The process of claim 1 whereinthe nonionic amphiphilic substance is selected from the group consistingof(1) a straight or branched chain polyglycerol ether having theformulae ##STR5## wherein n represents a statistical average value of 1to 6 andR represents a saturated or unsaturated, straight or branchedchain aliphatic radical containing 12 to 30 carbon atoms, a hydrocarbongroup of a lanolin alcohol or a 2-hydroxyalkyl group of a long chainα-diol; (2) a polyoxyethylenated fatty alcohol or polyoxyethylenatedsterol; (3) an oxyethylenated or nonoxyethylenated polyol ester; (4) anatural or synthetic glycolipid; or (5) an ether or ester of a polyolcontaining two alkyl groups having at least 8 carbon atoms, as thehydrophobic residue.
 7. The process of claim 1 wherein saidwater-immiscible liquid phase is added to said dispersion of spheres insaid continuous aqueous phase.
 8. The process of claim 1 wherein saidwater-immiscible liquid phase L is a compound having a molecular volumeof at least 200 cm³ /mol.
 9. The process of claim 1 wherein saiddispersion of spheres contains from 2 to 10 percent by weight of saidamphiphilic substance, relative to the total weight of the dispersion.10. The process of claim 1 wherein a single water-immiscible liquidphase is dispersed in the continous aqueous phase.
 11. The process ofclaim 1 wherein the dispersion of spheres in the continuous aqueousphase D is obtained by introducing the aqueous phase E into a liquidlipid to form a plane lamellar phase, adding the aqueous phase D andagitating the whole.
 12. The process of claim 1 in which in order toobtain the final dispersion the whole is agitated vigorously at aboutambient temperature.
 13. The process of claim 1 wherein said lipidconstituting the laminae of said spheres is an ionic or nonionic naturalor synthetic amphiphilic substance that contains, per molecule, one ormore long hydrocarbon chains and one or more hydroxyl, ether, carboxyl,phosphate, amine or ammonium groups.
 14. The process of claim 13 whereinthe ionic amphiphilic substance is a natural or synthetic phospholipid,a cationic or quaternary compound or an amphoteric or anionic compound.15. The process of claim 14 wherein the ionic amphiphilic substance isegg lecithin, soyalecithin, sphingomyelin,dipalmitoyl-phosphatidylcholine, hydrogenated lecithin, didodecyldimethylammonium chloride, distearyl dimethylammonium chloride,didodecyl dimethylammonium bromide or distearyl dimethylammoniumbromide.
 16. The process of claim 13 wherein the nonionic amphiphilicsubstance is selected from the group consisting of(1) a linear orbranched chain polyglycerol ether having the formulae ##STR6## wherein nrepresents a statistical average value of 1 to 6 andR represents asaturated or unsaturated, linear or branched chain aliphatic radicalcontaining 12 to 30 carbon atoms, a hydrocarbon group of a lanolinalcohol or a 2-hydroxyalkyl group of a long chain α-diol; (2) apolyoxyethylenated fatty alcohol or polyoxyethylenated sterol; (3) anoxyethylenated or nonoxyethylenated polyol ester; (4) a natural orsynthetic glycolipid; and (5) an ether or ester of a polyol containingtwo alkyl groups having at least 8 carbon atoms, as the hydrophobicresidue.
 17. The process of claim 1 wherein said continuous aqueousphase and said aqueous phase to be encapsulated in said spheres areisoosmotic.
 18. The process of claim 17 wherein said continuous aqueousphase and said aqueous phase to be encapsulated in said spheres areidentical.
 19. The process of claim 1 wherein the water-immiscibleliquid phase L is mixed with the dispersion of spheres in an amountranging from 2 to 70 percent by weight, relative to the weight of thedispersion.
 20. The process of claim 1 wherein the water-immiscibleliquid phase L is introduced into the dispersion of spheres in an amountranging from 20 to 2,000 percent by weight, relative to the weight ofsaid amphiphilic substance contained in said dispersion.